The retinoid (visual) cycle is a complex enzymatic pathway essential for regeneration of the visual chromophore, 11-cis-retinal, a component of rhodopsin and cone opsins that undergoes activation by light in vertebrate eyes. Maintaining continuous vision and preserving the health of photoreceptors requires an adequate continuing supply of this aldehyde so vertebrates evolved the retinoid cycle to achieve this objective. The pathway operates in both photoreceptor cells and the retinal pigmented epithelium (RPE), converting all-trans-retinal back to 11-cis-retinal by several chemical transformations. Whereas the classical vertebrate retinoid cycle contributes primarily to regeneration of rhodopsin in rod cells, RPE65-based chromophore production may also be important for cone function.
Inadequate availability and/or processing of vitamin A to the visual chromophore, 11-cis-retinal can adversely affect vertebrate rhodopsin regeneration and visual congenital or progressive blindness in humans. Inactivation of non-redundant enzymes of the retinoid cycle, e.g., either LRAT that esterifies all-trans-retinol or the retinoid isomerase called RPE65, produces Leber congenital amaurosis (LCA), a leading cause of inherited childhood blindness. LCA is an autosomal recessive, early onset severe retinal dystrophy that accounts for 5% of all inherited retinal dystrophies. Insufficient vitamin A in the diet also can lead to progressive deterioration of vision and ultimately blindness, a major problem in underdeveloped countries.
Whereas inadequate 11-cis-retinal production leads to congenital blindness in humans, accumulation of the photoisomerized chromophore all-trans-retinal also can be detrimental. Such is the case when this reactive aldehyde is not efficiently cleared from the internal membranes of retinal outer segment discs. Clearance of all-trans-retinal involves two steps: 1). Translocation of all-trans-retinal across the photoreceptor disc membranes by ATP-binding cassette transporter 4 (ABCA4), and 2). Reduction of all-trans-retinal to all-trans-retinol by retinol dehydrogenase 8 (RDH8), expressed in the outer segments of photoreceptors, and by RDH12 located in photoreceptor inner segments.
ABCA4, also known as ABCR or the rim protein, localizes to the rim of photoreceptor discs and transfers all-trans-retinal from the inside to the outside of disc membranes after it is released from visual pigments. Mutations in ABCA4 can cause Stargardt macular degeneration, cone-rod dystrophy, or recessive RP. Also, heterozygous mutations in ABCA4 increase the risk of developing age-related macular degeneration. Di-retinoid-pyridinium-retinylethanolamine (A2E) and retinal dimer (RALdi) conjugates are the major fluorophores of lipofuscins produced from all-trans-retinal. Even in the presence of a functional transporter, both A2E and RALdi can accumulate as a consequence of aging together with light exposure and produce toxic effects on RPE cells. Patients affected by age-related macular degeneration, Stargardt disease with a disabled ABCA4 gene or other retinal diseases associated with lipofuscin accumulation develop retinal degeneration. ABCA4 mutations also are linked to a high risk of AMD.